Method of protecting the skin against sunburn



y 14, 1964 M. SAHYUN 3,140,979

METHOD OF PROTECTING THE SKIN AGAINST SUNBURN Filed Aug. 4, 1960 l UV Tronsmission of O.2mM SO Solol and 2-Aminobenzoo1e in Water and Menlhyl Solicylole ln Alcohol FIG. I

lO- (Wilhoul UV filler) p-Aminobenzooie l l I l l 260 280 300 320 340 3&0

w 0.0lrnM UV Transmission of QOl-QZnnM aqueous Solutions of 2-(4-Dimelhylorninophenyl) imidozoline Dihydrochloride I04 (wim uv Filter) 260 290 aoo so 340 360 380 FIG. 2 INVENTOR MELVILLE SAHYUN BY spa-u.

ATTORNEY United States Patent Ofice 3,140,979 Patented July 14, 1964 3,140,979 METHOD OF PROTECTING THE SKIN AGAINST SUNBURN Melville Sahyun, Sahyun Laboratories, 316 Castillo St, Santa Barbara, Calif. Filed Aug. 4, 1960, Ser. No. 47,571 7 Claims. (Cl. l67--90) This invention relates to compounds which are strong absorbers of the ultra violet and more particularly to their use as protective agents against erythema or sunburn.

The radiant energies corresponding to the wave lengths of 2850 to 3100 Angstrom units are most effective in the causation or radiation burns or erythema. When the sun is the source of these frequencies, the resultant burning of the skin is known as sunburn. Thus in order to afford maximum protection against erythema or sunburn, the skin to be exposed should be coated with a material which is a strong absorber of ultra violet light particularly in the range of 2850 to 3100 Angstrom units.

It is an object of the present invention to provide a method for protecting the skin against erythema and sunburn.

I have discovered that certain tetrahydropyrimidine and imidazoline compounds, and their stable non-toxic acid addition salts and hydrates, are strong absorbers of ultra violet light with almost complete absorption in the critical 2850 to 3100 Angstrom unit range even in extremely dilute solution. These imidazoline and tetrahydropyrimidine compounds have the general formula:

R i H wherein R is hydrogen or lower alkyl and n is an integer having the values of 2 or 3, and are further described in US. Patent 2,733,244. In the practice of my invention, these compounds are dissolved in a solvent, such as water or alcohol, and applied to the area to be protected. Other appropriate solvents and solvent mixtures may be used but the aforementioned liquids are the most convenient and economical. The choice of solvent is not critical save that it be unreactive with respect to the ultra violet light absorbent used and not be harmful when applied to the skin. The absorbent solution is applied or rubbed into the skin or the absorbent is otherwise brought into intimate contact with and distributed over the skin to be protected on exposure to ultra violet radiation. Naturally the susceptibilities of various persons toward erythema and sunburning will differ but a concentration of the absorbents of this invention of at least 25 micrograms per square centimeter of skin surface will afford substantial protection in all cases. There is no theoretical upper limit to the amount of absorbent that may be used. Practical considerations teach that the minimum amount that is effective be used. Naturally somewhat larger amounts of the anti-ultra violet agent is to be used when the amount of exposure to ultra violet radiation is expected to be large.

It has been previously stated that ultra violet radiation having wave lengths between 2850 and 3100 Angstrom units is the most eifective in causing undesired erythema. This is illustrated in Table A which is based on data presented in Luckiesch and Taylor, General Electric Review, 42, 274 (1939).

TABLE A Wavelength in Erytherna Angstroms Etiectiveness 2, 850 D. 09 2. 900 D. 30 2,967 1. 0O 3, 022 0. 3.130 0. 03 3, 342 0. 00

FIGURE 1 illustrates the ultra violet absorption properties of three well known anti-ultra violet radiation agents currently in use, namely: phenyl salicylate (Salol), sodium p-aminobenzoate and menthyl salicylate. When their absorptive properties are compared with the absorptive properties of 2-(4-dimethylaminophenyl) imidazoline (illustrated in FIGURE 2) at the same 0.2 millimolar concentration, the eifectiveness of the latter in the important 2850 to 3100 Angstrom unit range is readily apparent. Further data illustrating the superior absorptive powers of solutions of 2-(4-aminophenyl) imidazoline, 2 (4 n propylaminophenyl) 3,4,5,5 tetrahydropyrimidine dihydrochloride and 2 (4 dimethyl' aminophenyl) imidazoline are given in the examples that follow:

Example I This example illustrates the selective ultra violet absorptive power of aqueous solutions of 2-(4-aminophenyl) imidazoline at the indicated millimolar concentrations (0.1 millimole equals 0.0179 gram per liter). The data recorded is the percent transmission at the indicated wavelengths with and without the use of a filter.

Percent Transmission Percent Transmission Without Filter With Filter Wavelength, Angstroms 0.1 0.05 0.01 0.01 0.05 0.01 mM. mM. 111M. mM. mM. mM.

18.2 43.8 85. 6 13.1 37.8 70.9 7. 6 28. 4 80. 2 5. 9 25. 1 75. 5 2.8 17.1 74. 3 0. 0 l2. 8 66. 9 2.1 13. 2 68. 0 0. 0 10.1 64. 8 1. 4 10. 4 07. 7 0. 0 7. 5 60. 9 0.1 8. 0 65. 8 0. 0 6. 5 59. 5 0. 6 8. 1 65. 9 0. 0 6. 5 58.9 0. 0 8. 2 66.1 0. 0 6. 3 61. 2 0.8 8.1 65.5 0. 0 6. 2 59. 2 0. 4 6. 2 64.4 0. 4 7.1 61.1 1.4 8.4 66.2 0.0 6.0 59.1 0. 7 8.5 66.0 0. 0 6.9 60. 0 0.8 0. 2 67.1 0. 0 6. 2 58.9 1.1 10.6 68.2 0. 0 8.0 62.0 1. 3 11.4 68. 7 0. 0 8.9 63. 8 3.0 14. 0 70. 5 0.1 10.5 66. 9 3.2 15. 7 72. 9 2.1 13. 5 6B. 8 5.9 19.5 74. 9 1.8 15. 0 70.2 4. 8 20. 2 75.8 3. 9 19. 1 73. 9 24. 4 49. 4 B8. 2 25. 2 48. 8 86. 9 66. 5 83. 9 96. 8 08. 2 83. 2 96. l 90. 7 96. 3 99. 0 91. 2 96.9 00. 0 95. 2 09v 4 99. 8 96. 2 99. 9 99.9 95. 6 99. 2 99. 7 96.0 99. 0 99. 0 3,8 96. 2 09. 9 99. 5 97. 2 100. 1 100. 1

Example I! This example illustrates the selective ultra violet absorptive power of aqueous solutions of 2-(4-n-propylaminophenyl 1 ,4,5 ,6-tetrahydropyrirnidine dihydrochloride at the indicated millimolar concentrations (0.1 millimole humans ure with one periments Percent Without Filter led in pound on the photographed untoward efgth, Transmission Angstroms pounds against ultra vio- The material to be osure of the forearm 95147918 5.121754234631927 Liamilian ZQWZKKZKLRWEQQQKKZ 42 3 15899 Example V Percent Transmission With Filter Percent gtb, Transmission Wavelen Without Filter 39 1.2349832313598833 2492 L95 2 1 LL Llew 1 431 11 11 4%%% Angstrems tion burns on skin has been stud Wavelen molar solution of menthyl salicylate in ethyl alcohol. The data recorded is the precent transmission at the indicated wavelengths measured without using a filter.

is the 0.0751111. 0.05mM. 0.01mM. 0.51J1M.

The data recorded icated wave lengths with 89.285225727003289 7888979 7 1513222 LLLLLZZLQUKiAmLuTEIB 31 158999 Percent Transmission Without Filter 85 69 507949 LZUUUO DUUUUUOODDOLiU 7 l 27%9W dihydrochloride at the indi- The data recorded is the percent ted wavelengths measured using Percent Transmission With Filter Example III dazol ica Example IV Wavelength, Angstroms equals 0.0290 gram per liter) percent transmission at the ind and without the use of a filter.

lml

t the ind henyl) ission a This example illustrates the selective ultra violet absorptive power of aqueous solutions of 2-(4-dirnethylaminop Wavelength,

Angstroms cated millimolar concentrations (0.1 millimole equals 0.0262 gram per liter).

transm a filter.

This example is given for comparative purposes and illustrates the ultra violet absorptive power of a 0.2 milli- 75 phenyl)-l,4,5,6-tetrahydropyr These examples illustrate the expected dependence of absorptive ability on concentration of the absorbent and further illustrate the substantially complete absorption of all radiation between 2850 and 3100 Angstrom units when the ultra violet absorber is present at a concentration of at least 0.1 or 0.2 millimolar.

2-(4-dimethylaminophenyl) imidazoline at similar concentrations.

This example illustrates that application of a solution containing an ultra violet absorbent of this invention to leave a surface concentration of absorbent of at least 25 micrograms per square centimeter of skin is effective to afford substantial protection against erythema or sunburn. In the usual practice of my invention, a solution of absorbent in an appropriate solvent is applied to the skin in an amount suflicient to give the desired surface concentration after evaporation of the solvent, or such a solution may be incorporated into a cream, lotion, emulsion or ointment suitable for topical application. Typical preparations would contain stearic acid, mineral oil or wax, petrolatum, fatty alcohol and emulsifying agents as well as the absorbent.

Example VI This example illustrates the beneficial properties of the compositions of the present invention by describing their use to stabilize organic compounds against the decomposition normally induced by ultra violet radiation. Only very small concentrations of the tetrahydropyrimidine and imidazoline compounds useful to prevent erythema or sunburn are capable of protecting solutions of organic amines from discoloration when subjected to sunlight radiation. Solutions containing one percent phenylephrine hydrochloride and epinephrine hydrochloride were prepared. Ten milliliters of one percent phenylephrine hydrochloride was introduced into each of eight test tubes. To four of this series, one milligram per milliliter of 2- 4-n-propylaminophenyl)-1,4,5,6-tetrahydropyrimidine dihydrochloride was added. Similarly eight test tubes, each containing milliliters of one percent epinephrine hydrochloride were prepared and to four of these test tubes, one milligram per milliliter of the same absorbent was added. All the test tubes were stoppered and exposed to full sunlight radiation during the month of June 1959. The samples were examined daily for disclororation. All test tubes containing phenylephrine hydrochloride and epinephrine hydrochloride without the anti-ultra violet agent began to discolor in about two days after sunlight exposure, whereas samples of phenylephrine hydrochloride and epinephrine hydrochloride with anti-ultra violet agent added remained clear and colorless. There was no visible discoloration after four weeks of continuous sunlight radiation exposure in the protected samples of phenylephrine hydrochloride, whereas the untreated samples turned dark purplish in color. In the samples of protected epinephrine hydrochloride, there was no visible discoloration for about two weeks of sunlight exposure in contrast to the untreated samples which turned dark purplish-brown in color.

The above examples are meant to be illustrative of the principles and methods employed in the practice of my invention and are not intended to limit its scope. Having described and illustrated my invention, I claim:

1. The method of protecting skin against sunburn which comprises applying thereto sufficient ultra violet absorbent material to absorb substantially all radiant energy in the 2850 to 3100 Angstrom unit range, said absorbent material being selected from the group consisting of compounds having the formula:

II N

wherein R is selected from the group consisting of hydrogen and lower alkyl and n is an integer having the values 2 and 3, and stable non-toxic acid addition salts and bydrates thereof.

2. The method of protecting skin against sunburn which comprises applying thereto at least 25 micrograms per square centimeter of an ultra violet absorbent material selected from the group consisting of compounds having the formula:

wherein R is selected from the group consisting of hydrogen and lower alkyl and n is an integer having the values 2 and 3, and stable non-toxic acid addition salts and hydrates thereof.

3. The method according to claim 2 wherein the active ingredient is incorporated into an ointment.

4. The method of protecting skin against sunburn which comprises (1) applying thereto a solution of an ultra violet absorbent material selected from the group consisting of compounds having the formula:

R N l wherein R is selected from the group consisting of hydrogen and lower alkyl and n is an integer having the values 2 and 3, and stable non-toxic acid addition salts and hydrates thereof, and (2) allowing the solvent to evaporate so that the concentration of the said absorbent material is at least 25 micrograms per square centimeter of skin to be protected.

5. The method according to claim 4 wherein the solution is aqueous.

6. The method according to claim 4 wherein the ultra violet absorbent is 2-(4-n-propylaminophenyl)-1,4,5,6- tetrahydropyrimidine dihydrochloride.

7. The method according to claim 4 wherein the ultra violet absorbent is 2-(4-dimethylaminophenyl) imidazoline dihydrochloride. 

1. THE METHOD OF PROTECTING SKIN AGAINST SUNBURN WHICH COMPRISES APPLYING THERETO SUFFICIENT ULTRA VIOLET ABSORBENT MATERIAL TO ABSORB SUBSTANTIALLY ALL RADIANT ENERGY IN THE 2850 TO 3100 ANGSTROM UNIT RANGE, SAID ABSORBENT MATERIAL BEING SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS HAVING THE FORMULA: 